The subject invention derives from the need to solve at least two related problems within the pharmaceutical industry: (1) inaccurate or inconsistent dose division upon breaking of a dosage form, and (2) inflexibility in adjusting the dose of only one active ingredient in a combination dosage form.
With regard to the first problem of inconsistent or inaccurate dose division, it is known that pharmaceutical tablets are commonly broken to modify the dose provided in a whole tablet. In the U.S., many “managed care” insurance organizations recommend or encourage patients to split or divide tablets, including unscored or irregularly-shaped tablets. These dosage adjustments, achieved through tablet breaking by patients, have been determined to be imprecise. No known solution to the problem has been provided.
Tablets are often produced with a score to aid breaking, but such tablet breaking is well-documented to suffer many problems whether or not scoring of the tablet is provided. Scored pharmaceutical tablets, layered or non-layered, fail to adequately address the problem because of uneven breaking, chipping, or crumbling that occurs upon breaking. Scores formed into a tablet have heretofore not exceeded 1 mm in depth.
In 1984, Stimpel, et al., found that tablet breaking was not accurate, even if performed by a sophisticated, dexterous person. M. Stimpel, et al., “Breaking Tablets in Half.” The Lancet (1984):1299.
In a report by Peek et al., “elderly patients” aged 50-79 using, without specific instruction, mechanical tablet splitters to break scored tablets produced highly unsatisfactory division of the tablets. Peek, B. T., Al-Achi, A., Coombs, S. J. “Accuracy of Tablet Splitting by Elderly Patients,” The Journal of the American Medical Association 288 No. 4 (2002):139-145. Many drugs, such as warfarin, require dosage adjustments. Peek, et al. found warfarin 5 mg was, on average, split into 1.9 and 3.1 mg tablets. This potent anticoagulant has such a narrow therapeutic range that 2, 2.5, and 3 mg tablet doses are manufactured. Biron, et al., demonstrated that warfarin 10 mg also often split to less than 4.25 or greater than 5.75 mg. Biron, C., Liczner, P., Hansel, S., Schved, J. F., “Oral Anticoagulant Drugs: Do Not Cut Tablets in Quarters,” Thromb. Haemost. 1201 (1999). In addition, a statistically significant loss of mass resulted from crumbling or chipping when breaking the warfarin tablets.
Rodenhuis, et al., observed that, in 1998, European regulatory authorities started a policy to discourage scoring of tablets. N. Rodenhuis et al., “The rationale of scored tablets as dosage form.” European J. of Pharmaceutical Sciences 21 (2004):305-308. Rodenhuis, et al., attributed the new policy to reports of “bad functioning score lines,” “tablets difficult to break,” and “unsatisfactory mass uniformity of the subdivided halves.” Rodenhuis, et al. noted that “[i]mproving the functioning of score lines may be a more practical approach than banning this [scored] dosage form”.
A second problem arising from dividing or breaking of tablets relates to combination drug products, i.e., single or unitary dosage forms containing two or more active ingredients. Combination dosage forms are typically produced as homogeneous mixtures or as capsules. A physician prescribing these homogeneously mixed combination products is unable to adjust the dose of only one of the active ingredients without a proportional adjustment to the dose of the other active ingredient(s). Even if the actives are layered separately, the layer configuration of currently available combination dosage forms results in dividing all layers, thus dividing all active ingredients proportionally. Combination dosage forms can thus be disadvantageous due to the inflexibility for dose adjustment. This disadvantage has hindered the acceptability of certain combination products. Nevertheless, combination treatments for hypertension have proven popular for cost and potential compliance reasons.
Combination products having at least two layers comprising active drug, and a third inactive layer are known. However, these dosage forms comprise the inactive layer interposed as a separating layer between the actives and only serve as a barrier between physical or chemical incompatible active drug-containing layers. The barrier layer does not serve as a means to enable a method of providing a partial dose of the drug or drugs in the combination product.
U.S. Pat. No. 5,738,874 to Conte, et al. describes a multi-layer controlled release tablet having a first layer comprising an immediate release drug composition, a second layer comprising a slow release drug composition, and a third layer comprising a barrier composition to modify release of drug from the adjacent layer. This third, drug-free layer is not interposed between the drug-containing layers and is not useful for facilitating breakage or splitting of the tablet to provide accurately divided doses.
US Patent Application, Pub. No. 2005/0019407A1 describes a composite dosage form having first and second portions joined at an interface. These dosage forms have a first molded material and a second compressed material. No disclosure is provided to teach or suggest modifying the dosage forms to facilitate the breaking or subdividing the dosage forms or providing a partial dose.
U.S. Pat. No. 6,602,521 describes a multiplex drug delivery system containing at least two immediate release drug dosage packages enveloped by a scored, extended release compartment. There is no teaching from the disclosure of this patent of a controlled release compartment which does not envelop the immediate release compartments.
Accordingly, there is a need for combination products which can provide the flexibility of adjusting the dose of one of the actives without necessarily adjusting the dose of the other active(s) contained within the combination dosage form.
The present invention, as disclosed herein, can overcome or alleviate the problems discussed above, and can provide additional advantages and address other problems as would be well understood and recognized from this disclosure by persons of ordinary skill in this art.